Background:Cerebral amyloid angiopathy (CAA) is a common pathological feature of patients with Alzheimer’s disease (AD) and is an important driver of vascular cognitive impairment and dementia (VCID). The unique properties of cerebral vascular amyloid and the distinct pathological pathways that it drives to promote VCID remain unknown. Here we investigated how cerebral vascular fibrillar amyloid seeds influence the assembly, accumulation and structure of Aß. Methods:Transgenic mouse models of cerebral vascular or parenchymal amyloid accumulation were used to measure cognitive performance. A combination of animal model and human brain tissues were used to extract cerebral vascular amyloid. Biochemical and biophysical approaches were used to identify distinct structural features of cerebral vascular amyloid. Primary cerebral cell cultures were utilized to investigate the unique functional properties of cerebral vascular amyloid that may underlie its contribution to cognitive impairment and dementia. Results: Transgenic mouse model of cerebral vascular amyloid exhibited earlier cognitive impairment compared to transgenic mouse model of parenchymal amyloid accumulation. Cerebral vascular amyloid extracted from transgenic mice, transgenic rats and human CAA exhibited an anti-parallel fibril signature that is distinct from the parallel fibril signature observed with parenchymal plaque amyloid. Cultured primary cerebral cells respond differently to amyloids with vascular or parenchymal signatures. Conclusions: These findings indicate that amyloid ß-protein fibrils isolated from different compartments in the brain exhibit different fibril signatures that can elicit distinct responses from cells that can uniquely contribute to cognitive impairment and dementia.